Colorectal cancer pathophysiology
Colorectal cancer Microchapters
Colorectal cancer pathophysiology On the Web
American Roentgen Ray Society Images of Colorectal cancer pathophysiology
To view the pathophysiology of familial adenomatous polyposis (FAP), click here
To view the pathophysiology of hereditary nonpolyposis colorectal cancer (HNPCC), click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D.  Associate Editor(s)-in-Chief: Saarah T. Alkhairy, M.D., Roukoz A. Karam, M.D., Elliot B. Tapper, M.D.
The pathogenesis of colorectal carcinoma (CRC) involves the molecular pathways for both sporadic and colitis-associated CRC. Sporadic instability originates from the epithelial cells that line the colon or rectum. Colitis-associated CRC includes genetic instability, epigenetic alteration, chronic inflammation, oxidative stress, and intestinal microbiota. According to the World Health Organization (WHO) histological classification, most colorectal tumors are carcinomas of which almost 90% are adenocarcinomas.
The pathogenesis of colorectal carcinoma (CRC) involves the molecular pathways for both sporadic and colitis-associated CRC.
Sporadic colorectal cancers
The picture below depicts the molecular pathogenesis of sporadic colon cancer:
- Produces the APC protein, which prevents the accumulation of β-catenin protein (responsible for stem cell renewal)
- Mutation of the APC protein leads to the accumulation of β-catenin protein and causes inappropriately high levels of stem cell renewal.
- Usually responsible for apoptosis, but deactivated in colorectal cancer
- Stimulate cellular division
- Mutations lead to over-activation of cell proliferation
Colitis-associated colorectal cancers
The picture below depicts the molecular pathogenesis of colitis-associated colon cancer:
- Genetic instability
- Chromosomal instability (CIN) occurs when either whole chromosomes or parts of chromosomes are duplicated or deleted; it occurs with 85% frequency.
- Microsatellite instability (MSI) is the condition of genetic hypermutability that results from impaired DNA mismatch repair; it occurs with 15% frequency.
- Epigenetic alteration
- Chronic inflammation
- Oxidative stress
- Oxidative stress results from inflammatory reactions which include inflammatory cells, activated neutrophils, and macrophages.
- Macrophages produce large amounts of reactive oxygen and nitrogen species.
- These reactive oxygen and nitrogen species can interact with key genes involved in carcinogenic pathways such as P53 and DNA mismatch repair genes.
- Intestinal microbiota
- The Modification of enteric flora by probiotic lactobacilli is a proposed mechanism that may contribute to the development of colitis-associated cancer.
From a genetic standpoint, colorectal cancer can be divided into three categories:
- Sporadic (75% of cases)
- No indication of a hereditary component
- Familial (20% of cases)
- Resulting from multifactorial hereditary factors and/or environmental exposures to non-genetic risk factors
- Hereditary (10% of cases)
- Hereditary nonpolyposis colon cancer (HNPCC) also known as Lynch Syndrome results from mutations in hMLH1, hMSH2, hMSH6, and PMS2
- Familial adenomatous polyposis (FAP) results from mutations in the APC gene located on chromosome 5p22.2
- MUTYH-associated polyposis (MAP) results from biallelic mutation of the MutY, E. Coli, Homolog gene which functions to remove adenine residues mispaired with 8-hydroxyguanine in DNA
- On gross pathology, a polypoid or fungating exophytic (growing outwards) lesion is characteristic of right-sided colorectal tumors including the ascending colon and cecum.
- Left-sided tumours tend to be circumferential and annular producing an "apple-core" appearance on barium enema x-ray.
According to the World Health Organization (WHO) histological classification, most colorectal tumors are carcinomas of which almost 90% are adenocarcinomas:
- Mucinous adenocarcinoma
- Signet-ring cell carcinoma
- Small cell carcinoma
- Adenosquamous carcinoma
- Squamous cell
- Medullary carcinoma
- Undifferentiated carcinoma
- Neuroendocrine neoplasms
- Mesenchymas tumors
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